Restenosis is a complex process which is believed to be triggered by blood vessel wall injury following an intervention to relieve an arterial obstruction (e.g., angioplasty, atherectomy, or stenting). Mechanisms contributing to restenosis include elastic recoil, smooth muscle cell migration and proliferation, enhanced extracellular matrix synthesis vessel wall remodeling, and thrombus formation (Haudenschild (1993) Am. J. Med. 94:40S-44S; Lovqvist, et al. (1994) J. Intern. Med. 233:215-226; Koster, et al. (1995) Angiology 46:99-106; Wilcox (1991) Circulation 84:432-435; Wilcox (1993) Am. J. Cardiol. 72:88E-95E; Wilcox and Blumenthal (1995) J. Nutr. 125:631S-638S). Restenosis after an initial successful angioplasty of an atherosclerotic plaque remains the major limitation of coronary angioplasty in humans.
Therapeutic approaches for the prevention of restenosis have focused on either intervening in early events, such as platelet deposition or thrombus formation, or preventing later events, i.e., proliferation of smooth muscle cells and matrix formation. Several classes of therapeutic agents have been used experimentally in animal studies. These have included anticoagulants, anti-inflammatory drugs, anti-platelet agents which can block initial events, and antiproliferative agents which inhibit the later events in the pathogenesis of restenosis (Herrman, et al. (1993) Drugs 46:18-52, 249-262; Marmur, et al. (1994) J. Am. Coll. Cardiol. 24:1484-1491; Mathias (1991) Semin. Thromb. Hemostat 17:14-20). Other approaches to treat restenosis have involved the use of antisense oligonucleotides to block transcription of certain cytokines or proto-oncogenes, such as c-myc or c-myb (Wilcox (1993) supra; Bennett, et al. (1994) J. Clin. Invest. 93:820-828; Epstein, et al. (1993) Circulation 88:1351-1353; Edelman, et al. (1995) Circ. Res. 76:176-182) Gene therapy strategies have also been investigated (Wilcox (1993) supra; Muller (1994) Br. Heart J. 72:309-312; Nabel, et al. (1990) Science 249:1285-1288; Nabel (1995) Cardiovasc. Res. 28:445-455; Bennett, et al. (1994) supra; Epstein, et al. (1993) supra; Edelman, et al. (1995) supra; Feldman and Isner (1995) J. Am. Coll. Cardiol. 26:826-835).
Modification of the restenosis process by conventional pharmacologic or mechanical approaches (e.g., stenting) (Wilensky, et al. (1993) Trends Cardiovasc. Med. 3:163-170) have been used in the clinical setting. Drug therapies have included antiplatelet and anticoagulant agents, calcium channel antagonists, inhibitors of angiotensin converting enzyme, corticosteroids, and fish oil diet (Herrman, et al. (1993) supra). Mechanical approaches include deployment of metallic or polymeric stents in the artery to inhibit elastic recoiling which usually occurs within hours following angioplastic procedure and results in renarrowing of the artery lumen (Herrman, et al. (1993) supra; De Scheerder, et al. (1995) Atherosclerosis 114:105-114; De Foley, et al. (1993) Am. Heart J. 125:686-694; Kuntz, et al. (1993) J. Am. Coll. Cardiol. 21:15-25; Lambert, et al. (1994) Circulation 90:1003-1011; Mitchel and McKay (1995) Cathet. Cardiovasc. Diagn. 34:149-154; Buchwald, et al. (1993) J. Am. Coll. Cardiol. 21:249-254). Other approaches include atherectomy, local treatment of arterial lesions with laser, thermal energy, and β- and γ-radiations following interventional procedures (Buchwald, et al. (1992) Am. Heart J. 123:878-885; Kouek, et al. (1992) Circulation 86:1249-1256; Israel, et al. (1991) J. Am. Coll. Cardiol. 18:1118-1119).
Administration of therapeutic agents at the site of arterial injury rather than by systemic administration has been discussed (Labhasetwar, et al. (1997) Adv. Drug Del. Rev. 24:63-85). Experimental studies in animal models of restenosis have been used to investigate local delivery of therapeutics for the prevention of restenosis (Lambert, et al. (1994) supra; Garcia, et al. (1990) Surg. Gynecol. Obstet. 171:201-205; Edelman, et al. (1990) Proc. Nat. Acad. Sci. USA 87:3773-3777; Edelman, et al. (1993) Proc. Nat. Acad. Sci. USA 90:1513-1517; Edelman and Karnovsky (1994) Circulation 89:770-776; Nathan, et al. (1995) Proc. Nat. Acad. Sci. USA 92:8130-8134; Okada, et al. (1989) Neurosurgery 25:892-898; Villa, et al. (1994) J. Clin. Invest. 93:1243-1249; Villa, et al. (1995) Circ. Res. 76:505-513). Adventitial drug implants (Edelman, et al. (1990) supra; Villa, et al. (1994) supra; Simons, et al. (1992) Nature 359:67-70; Simons, et al. (1994) J. Clin. Invest. 93:2351-2356), stents (Lincoff, et al. (1994) J. Am. Coll. Cardiol. 23:18A; Jeong, et al. (1994) Circulation 92:I37), and catheter-based delivery systems (Steg, et al. (1994) Circulation 90:1648-1656; Fernandez, et al. (1994) Circulation 89:1518-1522) have been disclosed. Further, Lanza, et al. ((2002) Circulation 106:2842) teach targeted paramagnetic nanoparticles containing paclitaxel for the prevention of restenosis after angioplasty.
U.S. patent application Ser. No. 09/847,945 teaches methods for treating hyperplasia in a subject by delivering at least one drug in nanoparticle form and dispersed in a biocompatible protein. This reference discloses the use of paclitaxel, rapamycin, steroids, and the like, as suitable candidates to inhibit proliferation and migration of cells. This reference does not teach block co-polymer nanoparticles.
U.S. Pat. No. 6,322,817 teaches a pharmaceutical formulation of paclitaxel, wherein the paclitaxel is entrapped into nanoparticles comprising at least one type of amphiphilic monomer which is polymerized by adding an aqueous solution of cross-linking agent. This reference discloses a preferred combination of amphiphilic monomers comprising vinyl pyrrolidone, N-isopropylacrylamide, and monoester of polyethylene glycol maleic anhydride cross-linked with a bi-functional vinyl derivative such as N,N′-methylene bis-acrylamide useful in the treatment of pathological conditions arising out of excessive proliferation of cells such as rheumatoid arthritis or cancer.
U.S. Pat. No. 6,759,431 discloses methods for treating or preventing diseases associated with body passageways by delivering to an external portion of the body passageway a therapeutic agent such as paclitaxel, or an analogue or derivative thereof encapsulated in polymeric carriers.
Intravenous or oral delivery of agents for preventing disease or conditions is generally ineffective because these routes of delivery do not provide a therapeutic dose of the agent to the target site for a prolonged period of time. Therefore, there is a need in the art for site-specific therapeutics to prevent the localized pathophysiologic process of select disease or conditions. The present invention meets this long-felt need.